New Drug Regimens Show Promise in Early and Late Myeloma

August 24, 2020

Treatment advances for multiple myeloma continue to bring improved outcomes for patients in different stages of their disease. Recent clinical trial reports show progress in treating two myeloma populations — newly diagnosed, transplant eligible patients, and individuals whose disease has progressed following several lines of therapy.

In one trial, the phase 2 GRIFFIN study showed that adding the drug daratumumab to a combination of bortezomib, lenalidomide, and dexamethasone achieved higher response rates in newly diagnosed patients who were eligible for high-dose therapy and autologous stem cell transplantation.

“The most important message is how the quality of responses was much higher with the integration of daratumumab, and improved over time,” says Paul G. Richardson, MD, clinical director of research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber, and senior investigator of the study.

The other trial, DREAMM-2, tested a recently developed investigational drug, belantamab mafodotin, in patients who had gotten worse despite treatment with immunomodulatory drugs, a proteasome inhibitor, and an anti-CD38 antibody. DREAMM-2 showed a clinically meaningful 31% overall response rate in these patients which proved durable with a median duration of response of 11 months.

In March 2020, belantamab mafodotin was granted priority review by the U.S. Food and Drug Administration for patients in this category. A very recent Oncology Drug Association Committee (ODAC) meeting in July — of which Richardson and Kenneth Anderson, MD, testified with DFCI patients — resulted in a unanimous vote for accelerated approval.

Paul Richardson, MD.

GRIFFIN study

The GRIFFIN study is a large randomized trial in newly diagnosed myeloma patients who were eligible for stem cell transplant.

The standard treatment for these patients is a combination of lenalidomide, bortezomib, and dexamethasone (RVd). The phase 2 GRIFFIN trial examined the effect of adding daratumumab, a humanized IgG-kappa anti-CD38 monoclonal antibody, to the standard three-drug RVd regimen.

In a report to the American Society of Hematology in 2019 and updated in a full publication of Blood this year, investigators demonstrated that the addition of daratumumab significantly improved rates of stringent clinical response and minimal disease negativity among patients with transplant-eligible newly diagnosed multiple myeloma. A total of 207 patients were included in the study, 30 of whom had high cytogenetic risk because of adverse chromosome abnormalities identified in their disease.

The study achieved its primary endpoint, as the addition of daratumumab to RVd improved the stringent complete response rate by the end of consolidation (42.4% vs. 32%). Daratumumab plus RVd achieved higher overall response (99% vs. 92%), very good partial response (91% vs. 73%), and complete response (52% vs. 42%) rates vs. RVd by the end of consolidation.

Researchers observed improvement in all patient subgroups, with the exception of those with ISS stage III disease or high cytogenetic risk, where the benefit appeared less robust than in other groups, suggesting more research for these patients with high risk features is warranted, and several candidate strategies for these patients are underway, Richardson commented.

“Overall, these results support the regimen as a potential new standard of care for this population,” Richardson noted.

Long term follow-up on the study is ongoing, with patients continuing maintenance therapy. Progression-free survival and overall survival data are immature but show “a very promising early signal,” Richardson says. Co-investigators and co-authors of the Blood paper at DFCI included Jacob Laubach MD, clinical director of the Jerome Lipper Multiple Myeloma Center.

DREAMM-2 study

This clinical trial was for patients whose myeloma has progressed after many previous treatments for myeloma, including an immunomodulatory drug and a proteasome inhibitor and were refractory or intolerant to an antibody that targeted the CD38 molecule.

The DREAMM-2 trial tested as a single agent an investigational drug, belantamab mafodotin. The drug is made up of an antibody that targets the B-cell maturation antigen, a protein present on the surface of myeloma tumor cells, linked to a synthetic anti-cancer drug that blocks cell division.

The results, published in The Lancet Oncology in December 2019, found an overall response rate — tumor shrinkage — of 31%. Of these responders, 18 patients had a very good partial response or better, including three patients with stringent complete or complete responses. Importantly, their responses proved durable with the most concerning adverse event being keratopathy — changes to the surface of the eye — in 27% of patients, but these proved reversible and generally manageable.

The authors concluded that belantamab mafodotin “shows anti-myeloma activity with a manageable safety profile in patients with relapsed and refractory multiple myeloma.” Richardson was a leading co-investigator and co-author on the report, with preclinical work on the antibody drug conjugate led by Yu-Tzu Tai, PhD, and Anderson.

Based on these data, On August 5, 2020, the U.S. Food and Drug Administration granted accelerated approval to belantamab mafodotin-blmf (Blenrep, GlaxoSmithKline) for adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.